Growth factors comprise a family of polypeptides with a manyfold of properties regulating for example cell proliferation and cell metabolism. As being multi-functional molecules, they may stimulate or inhibit cell proliferation as well as affect cell function depending on the type of the target cells and the presence of other signal peptides. The family of polypeptides include for example platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factors (TGF-, TGF-xcex2), insulin like growth factors (IGF-1, IGF-2), fibroblast growth factors (a FGF, b FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and bone morphogenetic proteins (BMP).
The activities of these growth factors are considered to be casual components of several conditions such as cardiovascular conditions, for example diabetes, inflammatory conditions for example rheumatoid arthritis, analgetic conditions, viral conditions, carcinogenic conditions, several eye diseases and wound healing.
Angiogenesis is under normal conditions under stringent control but in many pathological conditions e.g. solid tumours, rheumatoid arthritis, diabetic retinopathy and artherosclerosis unregulated vessel proliferation occurs. The angiogenetic process is controlled by a balance between many positive and negative regulating signals where growth factors such as TGF, FGF and VEGF play a dominant role.
Under normal conditions in the body growth factor activity is to a large extent regulated by the interactions with heparin and heparan sulfate. The interaction between these polyanionic glycosaminoglycans and growth factors is thought to be of functional significance serving as storage depots for growth factors and protecting them from various degradative processes (Vlodavsky, I., Fuks, Z., Ishai-Michaeli, R., Bashkin, P., Levi, E., Korner, G., Bar-Shavit, R., and Klagsbrun, M. (1991) J. Cell. Biochem. 45, 167-176).
Under some circumstances the administration of growth factors as therapeutic agents has been utilized. However the limited stability of this type of molecules reduces their activity before reaching the target in the body.
Under abnormal conditions when growth factor regulation is required to a larger extent than in the normal situation, the administration of heparin and derivatives of heparin has been considered. However the administration of these type of compounds renders side-effects like anticoagulant activity which limits their possible usage.
Other sulphonated compounds like suramin, a polysulphonated napthylurea, has been shown to have activity in the treatment of adrenocortical carbinoma but the limitation also for this type of compounds is the narrow margin between the dose required to achieve anti-tumor activity and the dose leading to the onset of toxic side effects.
According to the present invention the use of a compound containing a high density, negatively charged domain of vicinally oriented radicals for the preparing of a medicament providing a growth factor modulating activity in mammals including man is described.
The present invention more specifically relates to the use of these compounds in a method of treating angio genesis in tumor conditions.
In preferred embodiments of the invention the negatively charged domain comprises, at least three vicinal phosphorus-containing radicals,
The invention also relates to the use of a compound wherein the phosphorus-containing radicals have the following formula: 
wherein
V1 to V4are Y8m6To3U
To1 to To3 are (CH2)n, CHCH, or CH2CHCHCH2;
o1 to o3 are 0 or 1;
n is 0 to 4;
U is R1Y9m7, CY10Y11R2, SY12Y13Y14R3, PY15Y16Y17R4R5,
Y18PY19Y20Y21R6R7, CH2NO2, NHSO2R8, or NHCY22Y23R9;
m1 to m7 are 0 to 1;
Y1 to Y23 are NR10, NOR11, O, or S;
and where R1 to R11 are
i) hydrogen
ii) a straight or branched saturated or unsaturated alkyl residue containing 1-22 carbon atoms
iii) a saturated or unsaturated aromatic or non-aromatic homo- or heterocyclic residue containing 3-22 carbon atoms and 0-5 heteroatoms consisting of nitrogen, oxygen or sulfur
iv) a straight or branched saturated or unsaturated alkyl residue containing 1-22 carbon atoms substituted with a saturated or unsaturated aromatic or non-aromatic homo- or heterocyclic containing 3-22 carbon and 0-5 heteroatoms consisting of nitrogen, oxygen or sulfur
v) an aromatic or non-aromatic homo- or heterocyclic residue containing 3-22 carbon and 0-5 heteroatoms consisting of nitrogen, oxygen or sulfur substituted with a straight or branched saturated or unsaturated alkyl residue containing 1-22 carbon atoms. in the said groups ii-v the residues and/or the substituents the thereof being substituted with 0-6 of the following groups: hydroxy, alkoxy, aryloxy, acyloxy, carboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyl, carbamoyl, fluoro, chloro, bromo, azido, cyano, oxo, oxa, amino, imino, alkylamino, arylamino, acylamino, arylazo, nitro, alkylthio or alkylsulfonyl.
The streight or branched saturated or unsaturated alkyl residue in groups i-v above can be exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, doeicosyl, isopropyl, isobutyl, isopentyl, isohexyl, isoheptyl, isooctyl, isononyl, isodecyl, isodoecosyl, 2-butyl, 2-pentyl, 2-hexyl, 2-heptyl, 2-octyl, 2-nonyl, 2-decyl, 2-doeicosyl, 2-methylbutyl, 2-methylpentyl, 2-methylhexyl, 2-methylheptyl, 2-methyloctyl, 2-methylnonyl, 2-methyldecyl, 2-methyleicosyl, 2-ethylbutyl, 2-ethylpentyl, 2-ethylhexyl, 2-ethylheptyl, 2-ethyloctyl, 2-ethylnonyl, 2-ethyldecyl, 2-ethyleicosyl, tertbutyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, doeicosenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, doeicodienyl, ethynyl, propynyl, doeicosynyl.
The saturated or unsaturated aromatic or non-aromatic homo- or heterocyclic residue in groups i-v above can be exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, cyclooctadecyl, cyclononadecyl, cycloeicosyl, cycloheneicosyl, cyclodoeicosyl, adamantyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, phenyl, biphenyl, naphthyl, hydroxyphenyl, aminophenyl, mercaptophenyl, fluorophenyl, chlorophenyl, azidophenyl, cyanophenyl, carboxyphenyl, alkoxyphenyl, acyloxyphenyl, acylphenyl, oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, quinuclidinyl, dioxanyl, dithianyl, trioxanyl, furyl, pyrrolyl, thienyl, pyridyl, quinolyl, benzofuryl, indolyl, benzothienyl, oxazolyl, imidazolyl, thiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, purinyl, or a carbohydrate.
Substituents may be selected from the group of: hydroxy, alkoxy, aryloxy, acyloxy, carboxy, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyl, aryloxycarbonyloxy, carbamoyl, fluoro, chloro, bromo, azido, cyano, oxo, oxa, amino, imino, alkylamino, arylamino, acylamino, nitro, alkylthio, alkylsulfonyl.
Furthermore the invention relates to the use of a compound wherein the phosphorus-containing radicals have the following formula: 
wherein V1 and V2 are the same or different and are OH, (CH2) OH, COOH, CONH2, CONOH,
(CH2)pCOOH, (CH2)pCONH2, (CH2)pCONOH, (CH2)pSO3H, (CH2)pSO3NH2, (CH2)pNO2, (CH2)pPO3H2, O(CH2)pOH, O(CH2)pCOOH, O(CH2)pCONH2, O(CH2)pCONOH, O(CH2)pSO3H, O(CH2)pSO3NH2, O(CH2)pPO3H2 or CF2COOH
p is 1 to 4
In this embodiment of the invention the phosphorus-containing radicals are phosphonates or phospates or derivatives thereof.
In one embodiment of the invention the backbone to the high density negatively charged region of vicinally oriented radicals is a cyclic moiety.
The cyclic moiety comprises a saturated or unsaturated aromatic or non-aromatic homo- or heterocyclic moiety. When the moiety is heterocyclic the heteroatoms are selected from the group of oxygen, nitrogen, sulfur or selenium.
Preferably the cyclic moiety comprises 4 to 24 atoms, most preferably 5 to 18 atoms. The cyclic moiety is for example selected from the group of cyclopentane, cyclohexane, cycloheptane, cyclooctane, inositol, monosacharide, disacharide, trisacharide, tetrasacharide, piperidin, tetrahydrothiopyran, 5-oxotetrahydrothiopyran, 5,5-dioxotetrahydrothiopyran, tetrahydroselenopyran, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, 5-oxotetrahydrothiophene, 5,5-dioxotetrahydrothiophene, tetrahydroselenophene, benzene, cumene, meritylene, naphtalene and phenantrene. When the cyclic moiety is an inositol it could be selected from the group of alloinositol, cisinositol, epiinositol, D/L-chiroinositol, scylloinositol, myoinositol, mucoinositol and neoinositol.
In one preferred embodiment of the invention the compounds are phosphates, phosphonates or phosphinates of cyclohexane such as 1,2,3xcex2-cyclohexane-1,2,3-trioltrisphosphate.
In other preferred embodiments of this type of the invention the compounds are phosphates, phosphonates or phosphinates of inositol. Preferably the number of phosphate-, phosphonate- or phosphinate radicals per inositol moiety is at least three. The remaining hydroxyl groups on the inositol moiety may be derivatized in the form of ethers or esters.
In one preferred embodiment the compound is myo-inositol-1,2,6-trisphosphate or myo-inositol-1,2,3-trisphosphate.
In one most preferred embodiment the compounds are selected from the group of D-myo-inositol-1,2,6-trisphosphate, D-myo-inositol-1,2,6-tris(carboxymethylphosphate), D-myo-inositol-1,2,6-tris(carboxymethylphosphonate), D-myo-inositol-1,2,6-tris(hydroxymethylphosphonate), D-3,4,5-tri-O-methyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-hexanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-butanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-pentanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-isobutanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-propanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-(6-hydroxy-4-oxa)hexanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-3-(ethylsulphonyl)propanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-3-hydroxypropanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-(6-hydroxy)-hexanoyl-myo-inositol-1,2,6-trisphosphate, D-5-O-hexanoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-phenylcarbamoyl-myo-inositol-1,2,6-trisphosphate, D-3,4,5-tri-O-propanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphate), D-3,4,5-tri-O-butanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphate), D-3,4,5-tri-O-isobutanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphate), D-3,4,5-tri-O-pentanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphate), D-3,4,5-tri-O-hexanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphate), D-3,4,5-tri-O-propanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphonate), D-3,4,5-tri-O-butanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphonate), D-3,4,5-tri-O-iso-butanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphonate), D-3,4,5-tri-O-pentanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphonate), D-3,4,5-tri-O-hexanoyl-myo-inositol-1,2,6-tris(carboxymethylphosphonate), D-3,4,5-tri-O-propanoyl-myo-inositol-1,2,6-tris(hydroxymethylphosphonate), D-3,4,5-tri-O-butanoyl-myo-inositol-1,2,6-tris(hydroxymethylphosphonate), D-3,4,5-tri-O-isobutanoyl-myo-inositol-1,2,6-tris(hydroxymethylphosphonate), D-3,4,5-tri-O-pentanoyl-myo-inositol-1,2,6-tris(hydroxymethylphosphonate), D-3,4,5-tri-O-hexanoyl-myo-inositol-1,2,6-tris(hydroxymethylphosphonate).
When the cyclic moiety is a sacharide it could be selected from the group of D/L-ribose, D/L-arabinose, D/L-xylose, D/L-lyxose, D/L-allose, D/L-altrose, D/L-glucose, D/L-mannose, D/L-gulose, D/L-idose, D/L-galactose, D/L-talose, D/L-ribulose, D/L-xylulose, D/L-psicose, D/L-sorbose, D/L-tagatose and D/L-fructose or derivatives thereof. In preferred embodiments of this type of the invention the compounds are phosphates, phosphonates or phosphinates of sacharides. Preferably the number of phosphate-, phosphonate- or phosphinate radicals per sacharide unit is at least three. The remaining hydroxyl groups on the sacharide moiety may be derivatized in the form of ethers or esters. In many instances the ether form is desired as this type of radical propongs the stability and half-life in vivo as the susceptibility to enzymatic degradation is reduced. In one preferred embodiment of this type of the invention the compound is selected from the group of mannose-2,3,4-trisphosphate, galactose-2,3,4-trisphosphate, fructose-2,3,4-trisphosphate, altrose-2,3,4-trisphosphate and rhamnose-2,3,4-trisphosphate. In one most preferred embodiment the compound is selected from the group of R1-6-O-R2-xcex1-D-mannopyranoside-2,3,4-trisphosphate, R1-6-O-R2-xcex1-D-galactopyranoside-2,3,4-trisphosphate, R1-6-O-R2-xcex1-D-altropyranoside-2,3,4-trisphosphate and R1-6-O-R2-xcex2-D-fructopyranoside-2,3,4-trisphosphate where R1 and R2 independently are as defined above and preferably are methyl, ethyl, propyl, butyl, pentyl or hexyl. Most preferred compounds in this type of the invention are methyl-6-O-butyl-xcex1-D-mannopyranoside-2,3,4-trisphosphate, methyl-6-O-butyl-xcex1-D-galactopyranoside-2,3,4-trisphosphate, methyl-6-O-butyl-xcex1-D-glycopyranoside-2,3,4-trisphosphate, methyl-6-O-butyl-xcex1-D-altropyranoside-2,3,4-trisphosphate, methyl-6-O-butyl-xcex2-D-fructopyranoside-2,3,4-trisphosphate, 1,5-anhydro-D-arabinitol-2,3,4-trisphosphate, 1,5-anhydroxylitol-2,3,4-trisphosphate, 1,2-O-ethylene-xcex2-D-fructopyranoside-2,3,4-trisphosphate, methyl-xcex1-D-rhamnopyranoside-2,3,4-trisphosphate, methyl-xcex1-D-mannopyranoside-2,3,4-triphosphate, methyl-6-O-butyl-xcex1-D-mannopyranoside-2,3,4-tris-(carboxymethylphosphate), methyl-6-O-butyl-xcex1-D-mannopyranoside-2,3,4-tris-(carboxymethylphosphonate), methyl-6-O-butyl-xcex1-D-mannopyranoside-2,3,4-tris(hydroxymethylphosphonate), methyl-6-O-butyl-xcex1-D-galactopyranoside-2,3,4-tris(carboxymethylphosphate), methyl-6-O-butyl-xcex1-D-galactopyranoside-2,3,4-tris(carboxymethylphosphonate), methyl-6-O-butyl-xcex1-D-galactopyranoside-2,3,4-tris(hydroxymethylphosphonate), methyl-6-O-butyl-xcex1-D-glucopyranoside-2,3,4-tris(carboxymethylphosphate), methyl-6-O-butyl-xcex1-D-glucopyranoside-2,3,4-tris(carboxymethylphosphonate), methyl-6-O-butyl-xcex1-D-glucopyranoside-2,3,4-tris(hydroxymethylphosphonate), methyl-6-O-butyl-xcex1-D-altropyranoside-2,3,4-tris-(carboxymethylphosphate), methyl-6-O-butyl-xcex1-D-altropyranoside-2,3,4-tris-(carboxymethylphosphonate), methyl-6-O-butyl-xcex1-D-altropyranoside-2,3,4-tris-(hydroxymethylphosphonate), methyl-6-O-butyl-xcex2-D-fructopyranoside-2,3,4-tris-(carboxymethylphosphate), methyl-6-O-butyl-xcex2-D-fructopyranoside-2,3,4-tris-(carboxymethylphosphonate), methyl-6-O-butyl-xcex2-D-fructopyranoside-2,3,4-tris-(hydroxymethylphosphonate).
In other preferred embodiments of the invention the compounds are phosphates, phosphonates or phosphinates of heterocyclic moieties such as 1,5-dideoxy-1,5-iminoarabinitol-2,3,4-trisphosphate, 1,5-dideoxy-1,5-iminoarabinitol-2,3,4-tris-(carboxymethylphosphate), 1,5-dideoxy-1,5-iminoarabinitol-2,3,4-tris(carboxymethylphosphonate), 1,5-dideoxy-1,5-iminoarabinitol-2,3,4-tris(hydroxymethylphosphonate), 1,5-dideoxy-1,5-imino-N-(2-phenylethyl)arabinitol-2,3,4-trisphosphate, 1,5-dideoxy-1,5-imino-N-(2-phenylethyl)arabinitol-2,3,4-tris(carboxymethylphosphate), 1,5-dideoxy-1,5-imino-N-(2-phenylethyl)arabinitol-2,3,4-tris-(carboxymethylphosphonate), 1,5-dideoxy-1,5-imino-N-(2-phenylethyl)arabinitol-2,3,4-tris(hydroxymethylphosphonate).
The growth factor modulating activity of the described compounds are expressed on at least four levels. One level is a type of interaction with growth factors such as heparin-binding growth factors and/or the specific receptors of these growth factors. The compounds according to the invention interact with domains comprising high basicity on the growth factors. This type of interaction is considered to be an important factor in connection with growth factors such as basic fibroblast growth factor, acidic fibroblast growth factor, platelet-derived growth factor, vascular endothelial growth factor and hepatocyte growth factor.
The interactions are considered to be especially important in connection with growth factors from the fibroblast growth family such as different types of acidic and basic fibroblast growth factors. Processes which are regulated by the interaction are e.g dimerization and interactions with receptors and ligands.
Another level of interaction is a more specific interaction with the internalisation process of a group of growth factors. Many growth factors are exerting their effect after internalisation to the intracellular domain. The pathway includes an interaction/binding of the growth factor to the external part of a transmembrane receptor. Binding is followed by endocytosis i.e. the formation of a vesicle which is transferred over the plasma membrane and released into the internal part of the cell. This process of internalisation is controlled by specific assembly proteins. One specific assembly protein, AP-2 is considered to be important in the internalisation process of this group of growth factors. Within the scope of the invention it is considered that the described compounds interact with the external receptor and an ion-channel connected to AP-2. The binding of this group of growth factors to their receptor is effected by interaction with receptor bound small monophosphorylated sugars such as mannose-phosphate. When the binding to the monophosphorylated sugar is reversed by the existence of compounds according to the invention, the binding of the growth factor is retarded or does not happen at all.
The other interaction on this level is the binding of the compounds according to the invention to an ion-channel, most often a potassium-channel belonging to AP-2. Such a binding retards or in some case inhibit the internalisation process and thus retards or inhibits the consequences of growth factors entering the intenal part of the cell and the subsequent metabolic events. To the group of growth factors functioning according to the described pathway belong for example epidermal growth factor, transforming growth factor, insulin growth factor and nerve growth factor.
A third level of interaction includes a very specific interaction between the compounds according to the invention and a specific group of growth factors. The negatively charged domain of the compounds according to the invention interacts with domains in the growth factor, characterized by the existence of basic amino acids such as arginine, lysine and histidine structurally arranged in a way that renders condensed binding sites on a small area. The binding area is typically not exceeding 500 square Angstrom and requires a specific stereochemistry of the binding compound. Accordingly the preferred compounds have two equatorial and one axial equatorial negatively charged groups attached to a cyclic moiety. Within this group of growth factors transforming growth factor xcex2 is mentioned as one example. The interaction is for example expressed by three lysine moieties, lysine 25, lysine 31 and lysine 37 and three phosphate radicals in a way that the distance between the radicals is less than 10 Angstrom.
The interaction between the growth factors and the compounds according to the invention is characterized by a binding constant, KD. Typically, the KD-value is less than 100 xcexcM. Preferably the binding constant is less than 60 xcexcM and most preferably less than 30 xcexcM.
The interaction is also described as a consequence of the acid constants, pKA1 of the compounds according to the invention. Typically pKA1 is in the range of 7 to 9 and for some compounds in the range of 7 to 12.
A fourth level of interaction is expressed by a receptor interaction on the cell surface which transfer the signal from for example a specific growth factor via a signalling cascade to the internal compartments of the cell. The compounds bind to the receptor on the cell surface characterized by a IC50-value less than 50 xcexcM and preferably less than 5 xcexcM. The binding is depending on the concentration, either allosteric or hyperbolic.
The effects described renders the growth factor modulating activity which is characteristic to the use of the compounds according to the invention.
According to the invention the compounds are most often present in a salt form or in a form where only a few of the negative charges are protonated. The salt can contain one or more cations in different combinations. Examples of cations are sodium and potassium ions.
The pharmaceutical composition according to the invention may be adminstered orally, topically, parentally, rectally or by inhalation spray in dosage forms or formulations comprising conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
The pharmaceutical composition for oral use can be present in different forms such as capsules, granules, tablets, troches, lozenges, aqueous suspensions, dispensible powders, emulsions, syrups or elixirs. When the composition is present in liquid form capsules are preferably utilized. At the use of granules, these preferably have a size of 0.15-2 mm. Either the granules can consist of the pharmaceutical composition per se or of the composition and suitable fillers. When the pharmaceutical composition is used in a tablet form, the tablets can have a weight of 50-1500 mg, preferably 50-800 mg and most preferably 100-500 mg.
Formulations for oral use include tablets which contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, potato starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the activ ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
For the parentaral application of the composition of this invention, typical dosage forms include intravenous, intramuscular, intraperitoneal formulations
For the rectal application of the composition of this invention, typical dosage forms include suppositories, rectal gelatin capsules (solutions and suspensions), and enemas or micro-enemas (solutions and suspensions). Thus, in a typical suppository formulation, any one of the compounds of this invention is combined with any pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids, glycerinated gelatin, and various water-soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid ester. Various additives like salicylates or surfactant materials may be incorporated.
For topical use, creams, ointments, gels, solutions or the like containing the compostions are employed according to methods recognized in the art.
Naturally, the therapeutic dosage range for the compounds of the present invention will vary with the size and needs of the patient and the particular condition or disease symptom being treated.
The administration of the pharmaceutical composition according to the invention can be in a combined dosage form or in separate dosage forms.
For administration to human patients appropriate dosages can routinely be determined by those skilled in this art by extension of the results obtained in animals at various dosages. The preferred dosage for humans falls within the range of 0.1 to 100 mg compound per day and kg bodyweight, especially 0.1 to 50 mg/day/kg bodyweight.
The administration of the compounds according to the invention to mammals are considered to be benefical within the following conditions:
Bone disorders such as heterotopic ossification, osteoporosis, osteoarthritis, osteomalacia, Paget""s disease
Inflammatory conditions such as rheumatoid arthritis
Analgesic conditions such as hyperalgesia
Tumour conditions such as glioma, prostate cancer and other conditions where inhibition of angiogenesis is crucial
Wound healing or tissue repair such as matrix formation, collagen synthesis and scarr formation
Viral conditions such as HIV
Cardiovascular conditions such as atherosclerosis
Eye diseases
Infectious conditions such as trypanosomiasis
According to the present invention a process of modulating growth factor activity by using a compound containing a high density, negatively charged domain of vicinally oriented radicals is described.
In preferred embodiments of the invention the negatively charged domain comprises at least three vicinal phosphorus-containing radicals.
The invention also relates to the use of a compound wherein the phosphorus-containing radicals have the following formula: 
as described above.
The invention will be further explained with the following embodiment examples however without limiting it thereto.
Example 1 and 2 describe the interaction between growth factors and D-myo-inositol-1,2,6-trisphosphate (IP3). In example 3 and 4 the growth factor modulating effect of IP3 in tumor models are illustrated while example 5 describes the counteraction of heterotopic bone formation by IP3.
Example 6 shows the inhibitory effect of D-3,4,5-tri-O-hexanoyl-myo-inositol-1,2,6-trisphosphate (PP10-202) on HIV-infection.
Example 7 describes a growth factor modulating effect of IP3 in oedema conditions while example 8, 9 and 10 illustrate the growth factor modulating effect of 1,2-O-ethylene-xcex2-D-fructopyranoside 2,3,4-trisphosphate (PP 35-405), 1,5-dideoxy-1,5-imino-N-(2-phenylethyl)arabinitol-2,3,4-trisphosphate (PP 35-508) and myo-inositol-1,2,6-tris(carboxymethylphosphonate) (PP 40-402), respectively in inflammatory conditions.
In example 11 the growth factor modulating effect of IP3 in eye opening of mice is examined.
The effect of the application of IP3 on scarring is shown in example 12. Example 13 describes the interaction between assembly protein-2 (AP-2) and IP3. Example 14 illustrates the binding of compounds accordings to the invention to spermine, while example 15 shows the analgetic effect of methyl-xcex1-D-rhamnopyranoside-2,3,4-trisphosphate (PP 35-406). Example 16 describes the effect of IP3 on PI 3xe2x80x2-kinase. The effect of IP3 against bone tumours is described in Example 17. Example 18 illustrates the inhibitory effect of IP3 against b FGF-inducted damages, while Example 19 describes the interaction between IP3 and different fibroblast growth factors in computer modelling experiments.